1. Field of the Invention
The present invention provides novel dihydroquinolines which are effective as LDL lowering agents and which also have antioxidant capacity.
2. Description of Related Art
It is generally recognized that high blood cholesterol levels are significant risk factors in cardiovascular disease.
It has been established that 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is the first rate limiting enzyme in the biosynthetic pathway for cholesterol, that inhibition of HMGR activity results in a decrease in serum total cholesterol and low density lipoprotein (LDL) cholesterol levels, and that a decrease in serum LDL-cholesterol levels is reflected in a reduction of plasma level of apolipoprotein B. (Brown, et al, J. Lipid Res, 21: 505-517 (1980)).
Tocotrienols have been shown to suppress HMGR resulting in the inhibition of cholesterol biosynthesis and a subsequent drop in LDL cholesterol, apolipoprotein B, thromboxane B.sub.2, platelet factor 4 and glucose levels. (Wright, et al, A Symposium On Drugs Affecting Lipid Metabolism, Houston, Tex. (Nov. 1989)).
The tocotrienols are structurally related to the tocopherols (vitamin E) and differ only by possessing unsaturation in the isoprenoid side chain. Like the tocopherols, the tocotrienols have antioxidative activity. (Yamaoka, et al, Yukagaku, 34: 120-122 (1985); Serbinova, et al, Free Radical Biology and Medicine, 10: 263-275 (1991)).
Active oxygen species are known to play pivotal roles in the genesis of atherosclerotic plaques, thrombotic episodes, ischemic damage, cancer, aging, dementia, and inflammatory conditions. (Sies, H., Oxidative Stress; Academic Press, New York, (1985); Santrucek, M., Krepelka, J., Drugs of the Future, 13: 973-996 (1988); Steinberg, Circulation, 84: 1400-24 (1991)). Of particular interests are the potential protective effects of antioxidants on lipoproteins, since oxidized LDL is thought to be atherogenic. (Buckley et. al., Drugs, 37: 761-800 (1989); Gwynne et. al., Am. J. Cardiology, 62: 1B-77B (1988)).
PROBUCOL (4,4'-[(1-methylethylidene)bis(thio)]-bis[2,6-bis(1,1-dimethylethyl)](Lore lco, Marion Merrell Dow)(Formula I) is a hypolipidemic drug, which is also an excellent antioxidant. PROBUCOL inhibits the oxidative modification of LDL both in vitro and in vivo. (Steinberg, Am. J. Cardiol., 57: 16H-21H (1986)). PROBUCOL, however, suffers from bioavailability problems, exhibits only modest reductions in LDL cholesterol, and has undesirable effects on HDL cholesterol. ##STR1##
Esterbauer et al. (Dieber-Rotheneder, et al., J. Lipid Res., 32: 1325-32 (1991)) have examined the oxidative resistance of LDL as a function of oral vitamin E supplementation. While the oxidative resistance of LDL was significantly enhanced during vitamin E supplementation, antioxidant effectiveness varied considerably from subject to subject.
6-Ethoxy-2,2,4-trimethyl-3,4-dihydroquinoline (ETHOXYQUIN, Tokyo Kasai) is widely used as a feed preservative marketed under the name of SANTOQUIN [Formula II]. This antioxidant chemotype has been incorporated into retinoic acid derivatives, and were evaluated as a cancer-prevention agents. (Welch, et al., J. Med. Chem., 25: 81-84 (1982)). The water soluble analogue MTDQ-DA [Formula III] has been investigated as a antiatherosclerotic drug in cholesterol fed rabbits. (Pollak-Bar, et al., Fat Science Proc., 16th ISF Congress, 1059-1067 (1983)). MTDQ-DA mediated fairly modest effects on various lipid parameters, however this compound completely inhibited plaque progression relative to the cholesterol fed rabbit controls. ##STR2##
While the causative factors in the development of atherosclerosis are many, two important ones are elevated serum cholesterol levels and excessive LDL oxidation.
The above compounds do not successfully unite lipid lowering and antioxidant potential. The present invention describes the successful union of these two pharmacological properties in dihydroquinolines.